Cervical cancer screening programs are effective in preventing cancer and reducing mortality (1); however, there are limitations. Cervical cancer and the pre-malignant lesions (cervical intraepithial neoplasia grades I-III, corresponding to mild, moderate and severe dysplasia) are caused by the human papilloma virus (HPV) (2, 3). Most women who acquire HPV develop transient or subclinical infections (4, 5); very few women with HPV infections will progress to cervical intraepithial neoplasia grade II or III (CIN II or III) or cancer (4, 6-7). The major limitations of cervical cancer screening programs arise from the fact that Papanicolaou (Pap) smears and even biopsy can not distinguish benign transient HPV infections from those HPV lesions that will progress (4,7,8). Annually in the United States approximately 50 million women receive Pap smears (9); this results in 3.5 million women requiring follow-up cytology or further colposcopic evaluation for cytologic abnormalities (10). Yet, most of the women diagnosed with minor cytologic abnormalities will have an abnormal pap smear due to a self limiting HPV infection (4, 8). The cost attributed to the follow up of an abnormal Pap smears and the treatment of cervical neoplasia in the United States in 2000 was $2.7 billion (11).
Treatment of cervical neoplasia is costly, since patients referred to colposcopy that are diagnosed with low grade cervical lesions (CIN grade I or HPV infection) continue to be problematic even after biopsy. Again there are no clinically approved methods to distinguish transient HPV infection from HPV lesions that will become precancerous or cancerous (8). Therefore, all women diagnosed with cervical intraepithelial neoplasia grade I or HPV infections after colposcopy and biopsy require follow up. Current management guidelines for the treatment of CIN require that all patients follow one of the recommended protocols (12). These include cytology, colposcopy, and combinations of cytology and colposcopy and HPV DNA typing at various intervals (12, 13). These recommendations are supported by key medical associations including the American College of Obstetrics and Gynecology (12). The diagnosis of CIN grade 1 or HPV infection leads to multiple medical office visits and various repeat tests having to be performed to ensure that patients do not progress to higher grade lesions or cancer. However, it is well known that only 10% of patients with low grade lesions (CIN I or HPV infection) will subsequently develop CIN II, III or cancer in the next 2-years (14). Most patients with low-grade lesions will spontaneously regress (60%) and the remaining will have persistent disease (7, 13). Colposcopy and directed biopsy, which is the standard of care, is not sensitive in predicting disease outcomes in patients with CIN I or HPV infected lesions (15, 16). Furthermore, some clinicians tend to over treat these low grade lesions when they become persistent on repeat colposcopy and biopsy. The concern is that these patients may develop high grade dysplasias and it is difficult to identify these women with available tests. However, current methods used for the treatment of CIN can have clinical consequences especially in young women. Studies show that both ablative and excisional modalities used on the cervix can lead to an increased risk of preterm delivery, low birth weight and premature rupture of membranes (17, 18, 19). In recent years HPV DNA typing for oncogenic strains has been introduced into cervical cancer screening programs. However, up to 85% of patients with low grade cervical lesions will have high-risk HPVs identified making stratification difficult based on type alone (20).
Therefore, to date cervical cancer screening programs suffer from several limitations. Most of these limitations result from the inability of current clinically approved methods to distinguish transient HPV infections from true premalignant cervical lesions. The inability of current laboratory methods to distinguish these two entities affects Pap smear screening. It leads to high number of abnormal cases diagnosed with minor cytologic abnormalities (8). These abnormal pap smears then result in an excessive number of referrals for colposcopy and biopsy (21). Cases that are confirmed on colpscopy to be low grade lesions then require multiple office visits and testing for surveillance (12). Finally, some women with persistent low grade disease tend to be over treated for concerns of progression. The treatment modalities used are now recognized as having potentially serious consequences on future pregnancies, since they can affect normal cervical function (17, 18). Clearly, there is a need to improve current laboratory methods to reduce excessive costs, invasive testing and burden and risks to patients.